Polysubstituted pyrimidines inhibiting the formation of prostaglandin e2, a method of production thereof and use thereof

ABSTRACT

The invention describes the pyrimidine-based compounds of the general formula I. Described compounds lower the production of the prostaglandin E 2 . In concentrations lowering production of this factor by 50%, these compounds have no negative effect on the cell viability and they are not cytotoxic. Furthermore, the method of production of the compounds of the general formula I is provided. A pharmaceutical composition comprising the polysubstituted pyrimidines according to the invention and the use of these compounds for the treatment of the inflammatory diseases are also provided.

FIELD OF THE INVENTION

The present invention relates to polysubstituted pyrimidines and theirusage as prostaglandin E₂ production inhibitors.

PRIOR ART

Prostaglandin E₂ (PGE₂) is a lipid-like prostanoid. It is biosynthesizedvia a cascade of enzymatic reactions from arachidonic acid (Park, J. Y.,Clin. Immunol. 2006, 119, 229-240). During the normal state of theorganism, the PGE₂ shows homeostatic properties. During the pathologicalstate, the production of PGE₂ is induced via proinflammatory cytokines(e.g. interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α) andinterferon-γ (IFN-γ) (Dinarello, C. A., Chest 2000, 118, 503-508). Asthe consequence PGE₂ shows inflammatory properties.

Arachidonic acid is a substrate for enzyme cyclooxygenase (constitutivecyclooxygenase COX-1 and inducible COX-2). The COX transformsarachidonic acid into prostaglandin H₂ (PGH₂). The terminal enzyme inthe process is microsomal prostaglandin E₂ synthase (mPGES-1). ThemPGES-1 transforms the PGH₂ to PGE₂. Similarly to COX-2, the mPGES-1 isan inducible enzyme. Both COX-2 and mPGES-1 are induced by the samestimuli.

It has been shown that the proinflammatory factors (e.g. pain, swelling,fewer and redness) are lowered if the production of induced PGE₂ isinhibited. Commonly used PGE₂ production inhibitors are glucocorticoids,nonsteroidal anti-inflammatory drugs (NSAIDs, nonselective inhibitors ofCOX-1 and COX-2) and lately, so-called “coxibs” (selective COX-2inhibitors). Unfortunately, all the above-mentioned strategies showsevere side effects. The glucocorticoids are immunosuppressive, NSAIDscause gastrointestinal tract damage and the “coxibs” causecardiovascular issues. Therefore there is a dire need for thedevelopment of new PGE₂ production inhibitors with less or no sideeffects and possibly with a new mode of action.

Substituted pyrimidines show a wide range of biological activity (Sahu,M., Int. J. Pharm. Pharm. Sci. 2016, 8, 5, 8-21). From the literature,few examples are known of polysubstituted pyrimidines withanti-inflammatory properties. Pyrimidine substituted urea motives wereused as inhibitors of proinflammatory cytokines TNF-α and interleukin-6(Keche, A. P., Bioorg. Med. Chem. Lett. 2012, 22, 3445-3448).2,4-Diamino-5-cyclopropylpyrimidines were published as inhibitors ofTBK1/IKK₂₄₉ kinases regulating transcription processes related to theproduction of proinflammatory cytokines (McIver, Bioorg. Med. Chem. Lett2012, 22, 7169-7173). Suitably substituted dihydropyrimidines weredescribed as inhibitors of the mPGES-1, the key enzyme in the PGE₂biosynthesis (Lauro, G., Eur. J. Med. Chem 2014, 80, 407-415). Thepirinixic acid derivatives showed activity as dual inhibitors of mPGES-1and 5-lipoxygenase (5-LO) (Hanke, T., J. Med. Chem. 2013, 56,9031-9044).

In our laboratory, the polysubstituted pyrimidines were discovered,patented and lately published serving as dual inhibitors of productionof PGE₂ and nitric oxide (NO) (Jansa, P. WO2012116666 2012, A1; U.S.Pat. No. 8,883,798); Jansa, P. Med. Chem. Res. 2014, 23, 4482-4490;Jansa, P. Med. Chem. Res. 2015, 24, 2154-2166).

DISCLOSURE OF THE INVENTION

The aspect of this invention is the polysubstituted pyrimidine compoundsof general formula I,

wherein

X₁ to X₄ are the same or different substituents selected from the groupconsisting of —H, —F, —Cl, —OR, alkyl wherein R is hydrogen or asubstituent selected from the group of alkyl, alkenyl, alkynyl and arylas defined herein;

Y₁ and Y₂ are the same or different substituents selected from the groupconsisting of —H, —F, —Cl, —OR, —SR, —R, —CF₃ wherein R is hydrogen or asubstituent selected from the group consisting of alkyl, alkenyl,alkynyl and aryl, as defined herein;

R₁ is a substituent selected from the group consisting of alkyl,alkenyl, alkynyl, aryl as defined herein, with the proviso that alkyldoes not include methyl;

R₂ is alkyl as defined herein;

or a pharmaceutically acceptable salt thereof, wherein,

alkyl in these cases is defined as a linear or branched C₁-C₁₀ carbonchain in which any —CH₂— group can be replaced by a —O— or —S—substituent;

alkenyl in these cases is defined as a linear or branched C₁-C₁₀ carbonchain containing at least one double bond in which any —CH₂— group canbe replaced by a —O— or —S— substituent;

alkynyl in these cases is defined as a linear or branched C1-C10 carbonchain containing at least one triple bond in which any —CH₂— group canbe replaced by a —O— or —S— substituent;

aryl in the above cases is defined as a hydrocarbon group containing 6to 14 carbon atoms containing at least one aromatic ring wherein thearyl may be unsubstituted or substituted with 1 to 5 substituentsselected from the group of —F, —Cl, —OR, alkyl, wherein R is hydrogen ora substituent selected from the group consisting of alkyl, alkenyl, oralkynyl as defined herein.

More preferably, the invention relates to the following polysubstitutedpyrimidines of the general formula I:

5-butyl-4-(4-ethoxyphenyl)-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-isopropoxyphenyl)-6-phenylpyrimidin-2-amine,

5-butyl-4-phenyl-6-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine,

4-(4-(benzyloxy)phenyl)-6-phenylpyrimidin-2-amine,

4-(4-(benzyloxyphenyl)-5-butyl-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-(naphthalen-1-ylmethoxy)phenyl)-6-phenylpyrimidin-2-amine,

4-(4((4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-((4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine,

4-(4-(4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-((4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine,

4-(4-(benzyloxy)-2-methylphenyl)-5-butyl-6-phenylpyrimidin-2-amine,

4-(4-(benzyloxy)-2,3-difluorophenyl)-6-phenylpyrimidin-2-amine,

4-(4-(benzyloxy)-2,3-difluorophenyl)-5-butyl-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-((2-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine,

5-butyl-4-(4-((3-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine,

4-(4-(benzyloxy)phenyl)-5-butyl-6-(3-methoxyphenyl)pyrimidin-2-amine,

4-(4-(benzyloxy)phenyl)-5-butyl-6-(4-methoxyphenyl)pyrimidin-2-amine,

4-(4-(benzyloxy)phenyl)-5-butyl-6-(3-chlorophenyl)pyrimidin-2-amine,

4-(4-(benzyloxy)phenyl)-5-butyl-6-(4-chlorophenyl)pyrimidin-2-amine,

and their pharmaceutically acceptable salts.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts which are within reasonable medical judgment suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic reactions, and the like, and have anacceptable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the field, for example, P. H. Stahl and the coauthorsdescribed the pharmaceutically acceptable salts in detail in “Handbookof Pharmaceutical Salts Properties, Selection, and Use” (Wiley V C H,Zunch, Switzerland: 2002). Examples of such salts include but are notlimited to acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,hydroxyethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Also groups containinga nitrogen atom can be quaternized with agents such as lower alkylhalides such as methyl, ethyl, propyl and butyl chlorides, bromides andiodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides; arylalkyl halides such as benzyl andphenethyl bromides and others.

The subject of the present invention are furthermore the polysubstitutedpyrimidines of the formula I for use as pharmaceuticals.

The subject of the present invention is also the polysubstitutedpyrimidines of formula I for use as drugs which inhibit theoverproduction of prostaglandin E₂.

The subject of the present invention are also the polysubstitutedpyrimidines of the formula I for use as medicaments for the treatment ofdiseases which are induced or their severity is increased by theoverproduction of prostaglandin E₂, especially for the treatment ofinflammatory and/or cancerous diseases or as anti-angiogenic,immunomodulatory, an antiproliferative or anticancer drug.

It is also a subject of the present invention to use a substitutedpyrimidine of formula (I) as another active ingredient of apharmaceutical composition for the treatment of diseases which areinduced or their severity is increased by the overproduction ofprostaglandin E₂, in particular for the treatment of inflammatory and/ortumor diseases.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula Iand optionally at least one pharmaceutically acceptable carrier, fillerand/or diluent.

The subject of the present invention also provides a pharmaceuticalcomposition for use in the treatment of diseases which are induced ortheir severity is increased by the overproduction of prostaglandin E₂,in particular for the treatment of inflammatory and/or tumor diseases.

The term “therapeutically effective amount” as used herein refers to anamount of a compound or drug that is effective in “treating” a diseaseor disorder in a human or a mammal. In the case of cancer treatment, atherapeutically effective amount of a drug may reduce the number ofcancer cells; reduce tumor size; inhibit (i.e., to some extent slow downand preferably stop) the infiltration of cancer cells into theperipheral organs; inhibit, to some extent, and preferably stop, theformation of tumor metastases, inhibit, to some extent, tumor growthand/or to some extent alleviate one or more symptoms associated withcancer. Since the drug can prevent growth and/or kill existing cancercells, it may be cytostatic and/or cytotoxic.

The term “pharmaceutical composition” refers to the formulation of acompound and medium generally recognized in the art for delivery of abiologically active compound to a mammal, e.g., a human. Such a mediumincludes all pharmaceutically acceptable carriers, diluents orexcipients.

The term “pharmaceutically acceptable carrier, diluent or filler” asused herein includes, without limitation, any excipient, carrier,glidant, sweetener, preservative, dye, flavor enhancer, surfactant,dispersing agent, suspending agent, isotonic agent, solvent, oremulsifier that has been approved for use in humans or domestic animals

The invention further encompasses compounds of formula (I) foradministration as a single active ingredient of a pharmaceuticallyacceptable composition which can be prepared by conventional methodsknown in the art, for example by binding the active ingredient to apharmaceutically acceptable, therapeutically inert organic and/orinorganic carrier or excipient, or mixed therewith.

Another possibility is the use of a compound of formula (I) as a secondor other active ingredient having a synergistic effect with other activeingredients in known drugs, or administration of the compounds offormula (I) together with such drugs.

The compounds of formula (I) of the present invention may also be usedin the form of a prodrug or another suitably formulated form whichreleases the active ingredient in vivo.

The presented compounds of the general formula I differ from thepreviously published group of polysubstituted pyrimidines (Jansa, P.WO2012116666 2012, A1; U.S. Pat. No. 8,883,798). The previouslypublished compounds acted as the dual inhibitors of PGE₂ and NO. Theyalso lack the substitution on oxygen in position 4 of the C4-phenylring. This structural change leads to increased and selective inhibitionof PGE₂ without showing the NO inhibition. Currently published compoundsshow no or low inhibition of NO production and thus cannot be consideredas dual inhibitors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Overall effects of tested pyrimidine derivatives on theproduction of PGE₂ and NO by mouse peritoneal cells. The bars aremeans±95% limits of confidence averaged over effects of nineteen testedcompounds.

EXAMPLES LIST OF ABBREVIATION

DMSO dimethylsulfoxide

NMR nuclear magnetic resonance

HRMS high resolution mass spectrometry

EtOAc ethyl acetate

LPS lipopolysaccharide

LDH kit lactate dehydrogenase test kit

The range of the invention is not limited by the following examples.

TABLE 1 Overview of the compounds prepared in following examples.Compound Structure Nomenclature 1 1a

5-butyl-4-(4-ethoxyphenyl)-6-phenylpyrimidin-2- amine 2 1b

5-butyl-4-(4-isopropoxyphenyl)-6- phenylpyrimidin-2-amine 3 1c

5-butyl-4-phenyl-6-(3,4,5- trimethoxyphenyl)pyrimidin-2-amine 4 1d

4-(4-(benzyloxy)phenyl)-6-phenylpyrimidin-2- amine 5 1e

4-(4-(benzyloxy)phenyl)-5-butyl-6- phenylpyrimidin-2-amine 6 1f

5-butyl-4-(4-(naphthalen-1-ylmethoxy)phenyl)-6- phenylpyrimidin-2-amine7 1g

4-(4-((4-methoxybenzyl)oxy)phenyl)-6- phenylpyrimidin-2-amine 8 1h

5-butyl-4-(4-((4-methoxybenzyl)oxy)phenyl)-6- phenylpyrimidin-2-amine 91i

4-(4-((4-chlorobenzyl)oxy)phenyl)-6- phenylpyrimidin-2-amine 10 1j

5-butyl-4-(4-((4-chlorobenzyl)oxy)phenyl)-6- phenylpyrimidin-2-amine 111k

4-(4-(benzyloxy)-2-methylphenyl)-5-butyl-6- phenylpyrimidin-2-amine 121l

4-(4-(benzyloxy)-2,3-difluorophenyl)-6- phenylpyrimidin-2-amine 13 1m

4-(4-(benzyloxy-2,3-difluorophenyl)-5-butyl-6- phenylpyrimidin-2-amine14 1n

5-butyl-4-(4-((2-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine 15 1o

5-butyl-4-(4-((3-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine 16 2a

4-(4-(benzyloxy)phenyl)-5-butyl-6-(3- methoxyphenyl)pyrimidin-2-amine 172b

4-(4-(benzyloxy)phenyl)-5-butyl-6-(4- methoxyphenyl)pyrimidin-2-amine 182c

4-(4-(benzyloxy)phenyl)-5-butyl-6-(3- chlorophenyl)pyrimidin-2-amine 192d

4-(4-(benzyloxy)phenyl)-5-butyl-6-(4- chlorophenyl)pyrimidin-2-amine

Example 1 5-butyl-4-(4-ethoxyphenyl)-6-phenylpyrimidin-2-amine (1a)

The water-dioxane mixture was bubbled with argon for 5 minutes. Thestarting materials 5-butyl-4-chloro-6-phenylpyrimidin-2-amine (100 mg,0.38 mmol, 1 equivalent, synthesized according to Jansa, P. WO20121166662012, A1), 4-ethoxyphenylboronic acid (88 mg, 0.53 mmol, 1.4equivalent), Pd[P(Ph)₃]₄ (11 mg, 9.50 mmol, 0.025 equivalent) and Cs₂CO₃(310 mg, 0.95 mmol, 2.5 equivalent) were added. The reaction mixture wasstirred at 110° C. for 16 hours. The solvents were evaporated in vacuo.The crude reaction mixture was co-distilled twice with ethanol andpurified via silica gel column chromatography (eluent cyclohexane-ethylacetate, gradient 0 to 60%). The product was obtained as white amorphoussolid (yield 83 mg, 63%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.42 (m, 7H, ArH); 7.03-6.98 (m, 2H,ArH); 6.47 (s, 2H, NH₂); 4.08 (q, J=7.0 Hz, 2H, O—CH₂—CH₃); 1.36 (t,J=7.0 Hz, 3H, O—CH₂—CH₃); 1.02-0.92 (m, 2H, CH₂—CH₂—CH₂); 0.90-0.79 (m,2H, CH₂—CH₂—CH₃); 0.47 (t, J=7.3 Hz, 3H, CH₂—CH_(3).) ¹³C NMR (100 MHz,DMSO-d₆) δ 168.04; 167.60; 161.48; 158.97; 140.25; 132.30; 130.20;128.65; 128.42; 118.57; 114.23; 63.53; 32.18; 27.02; 22.02; 15.11;13.63. HRMS (ESI) m/z [M+H]⁺ calculated: C₂₂H₂₆N₃O 348.2070; found:348.2071.

Example 2 5-butyl-4-(4-isopropoxyphenyl)-6-phenylpyrimidin-2-amine (1b)

Compound 1b was prepared according to the procedure in Example 1 front5-butyl-4-chloro-6-phenylpyrimidin-2-amine (100 mg, 0.38 mmol, 1equivalent) and 4-isopropoxyphenylboronic acid (95 mg, 0.53 mmol, 1.4equivalent) as a white amorphous solid (yield 114 mg, 83%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.40 (m, 7H, ArH); 7.02-6.96 (m, 2H,ArH); 6.46 (s, 2H, NH₂); 4.69 (p, J=6.0 Hz, 1H, OCH—(CH₃)₂); 1.30 (d,J=6.0 Hz, 6H, OCH—(CH₃)₂); 1.03-0.92 (m, 2H, CH₂—CH₂—CH₂); 0.90-0.80 (m,2H, CH₂—CH₂—CH₃); 0.47 (t, J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz,DMSO-d₆) δ 168.02; 167.61; 161.48, 157.91; 140.26; 132.17; 130.23;128.64; 128.42; 118.57; 115.41; 69.66; 32.18; 27.00; 22.26; 22.02;13.59. HRMS (ESI) m/z [M+H]⁺ calculated: C₂₃H₂₈N₃O 362.2227; found:362.2227.

Example 3 5-butyl-4-phenyl-6-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine(1c)

Compound 1c was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (300 mg, 1.15 mmol, 1equivalent) and 3,4,5-trimethoxyphenylboronic acid (341 mg, 1.61 mmol,1.4 equivalent) as a white amorphous solid (yield 336 mg, 74%).

¹H NMR (400 MHz, DMSO-d6) δ 7.51-7.39 (m, 5H, ArH); 6.77 (s, 2H, ArH);6.51 (s, 2H, NH2); 3.80 (s, 6H, m-OCH3); 3.71 (s, 3H, p-OCH3); 2.49-2.45(m, 2H, HetAr—CH2—CH2); 1.08-0.97 (m, 2H, CH2—CH2—CH2); 0.94-0.83 (m,2H, CH2—CH2—CH3); 0.49 (t, J=7.3 Hz, 3H, CH2—CH3); ¹³C NMR (100 MHz,DMSO-d6) δ 168.10; 167.85; 161.41; 152.94; 140.16; 137.89; 135.60;128.69; 128.58; 128.43; 118.64; 106.19; 60.63; 56.47; 32.37; 27.19;22.17; 13.62. HRMS (ESI) m/z [M+H]⁺ calculated: C₂₃H₂₈N₃O₃ 394.2125;found: 394.2126.

Example 4 4-(4-(benzyloxy)phenyl)-6-phenylpyrimidin-2-amine (1d)

Compound 1d was prepared according to the procedure in Example 1 from4-chloro-6-phenylpyrimidin-2-amine (100 mg, 0.49 mmol, 1 equivalent) and4-benzyloxyphenylboronic acid (157 mg, 0.69 mmol, 1.4 equivalent) as awhite amorphous solid (yield 97 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.18 (m, 4H, ArH); 7.66 (s, 1H,HetArH); 7.55-7.47 (m, 5H, ArH); 7.45-7.33 (m, 3H, ArH); 7.18-7.13 (m,2H, ArH); 6.67 (s, 2H, NH₂); 5.21 (s, 2H, O—CH₂—Ar). ¹³C NMR (100 MHz,DMSO-d₆) δ 165.00; 164.82; 164.37; 160.78; 137.94; 137.30; 130.78:130.29; 129.02; 128.93; 128.39; 128.25; 127.39; 115.24; 101.54; 69.82.HRMS (EI) m/z calculated: C₂₃H₁₉N₃O 353.1528; found: 353.1526.

Example 5 4-(4-(benzyloxy)phenyl)-5-butyl-6-phenylpyrimidin-2-amine (1e)

Compound 1e was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (300 mg, 1.15 mmol, 1equivalent) and 4-benzyloxyphenylboronic acid (367 mg, 1.61 mmol, 1.4equivalent) as a white amorphous solid (yield 97 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.51-7.31 (m, 12H, ArH); 7.13-7.07 (m, 2H,ArH); 6.47 (s, 2H, NH₂); 5.17 (s, 2H, O—CH₂—Ar); 1.02-0.92 (m, 2H,CH₂—CH₂—CH₂), 0.90-0.78 (m, 2H, CH₂—CH₂—CH₃); 0.47 (t, J=7.3 Hz, 3H,CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.06; 167.54; 161.48; 158.78;140.24; 137.40; 132.67; 130.20; 128.90; 128.64; 128.42; 128.32; 128.21;118.59; 114.71; 69.71; 32.20; 27.03; 22.03; 13.63. HRMS (ESI) m/z [M+H]⁺calculated: C₂₇H₂₈N₃O 410.2227; found: 410.2229.

Example 65-butyl-4-(4-(naphthalen-1-ylmethoxy)phenyl)-6-phenylpyrimidin-2-amine(1f)

Compound 1f was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.76 mmol, 1equivalent) and 4-(naphthalen-1-ylmethoxy)phenylboronic acid (295 mg,1.06 mmol, 1.4 equivalent) as a white amorphous solid (yield 125 mg,36%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.23 (m, 1H, ArH); 7.92-7.87 (m, 1H,ArH); 7.66 (d, J=8.2 Hz, 2H, ArH); 7.58-7.40 (m, 11H, ArH); 7.10 (dd,J=7.7, 1.0 Hz, 1H, ArH): 6.53 (s, 2H, NH₂); 5.41 (s, 2H, O—CH₂—Napht);1.03-0.93 (m, 2H, CH₂—CH₂CH₂); 0.89-0.79 (m, 2H, CH₂—CH₂—CH₃); 0.45 (t,J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.12; 167.79;161.49; 154.08; 140.08; 139.61; 137.65; 134.54; 128.89; 128.72; 128.63;128.46; 127.98; 127.48; 126.95; 126.60; 125.89; 125.52; 121.99; 120.68;118.66; 106.41; 69.66; 32.25; 26.92; 22.02; 13.55. HRMS (ESI) [M+H]⁺ m/zcalculated C₃₁H₃₀N₃O 460.2383; found: 460.2383.

Example 7 4-(4-4(4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine(1g)

Compound 1g was prepared according to the procedure in Example 1 from4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.98 mmol, 1 equivalent) and4-(4-methoxybenzyl)oxy)phenylboronic acid (354 mg, 1.37 mmol, 1.4equivalent) as a white amorphous solid (yield 165 mg, 44%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.15 (m, 2H, ArH); 7.85 (t, J=2.7, 1.6Hz, 1H, ArH); 7.81 (d, J=7.6, 1.2 Hz, 1H, ArH); 7.71 (s, 1H, HetArH);7.56-7.50 (m, 3H, ArH); 7.47-7.40 (m, 3H, ArH); 7.16 (dd, J=8.1, 2.6,0.9 Hz, 1H, ArH); 7.01-6.94 (m, 2H, ArH); 6.75 (s, 2H, NH₂); 5.13 (s,2H, CH₂); 3.77 (s, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.34;165.05; 164.41; 159.21; 139.29; 137.79; 130.90; 130.12; 129.32; 129.05;127.47; 119.90; 117.31; 114.30; 113.74; 102.41; 69.64; 55.57. HRMS (EI)m/z calculated: C₂₄H₂₂ON₃ 384.17065; found: 384.17077.

Example 85-butyl-4-(4-((4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine(1h)

Compound 1h was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.76 mmol, 1equivalent) and 4-((4-methoxybenzyl)oxy)phenylboronic acid (274 mg, 1.06mmol, 1.4 equivalent) as a white amorphous solid (yield 261 mg, 78%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.38 (m, 9H, ArH); 7.11-7.06 (m, 2H,ArH); 6.98-6.94 (m, 2H, ArH); 6.47 (s, 2H, NH₂); 5.08 (s, 2H, O—CH₂—Ar);3.77 (s, 3H, OCH₃); 1.02-0.91 (m, 2H, CH₂—CH₂—CH₂); 0.90-0.79 (m, 2H,CH₂—CH₂—CH₃); 0.47 (t, J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz,DMSO-d₆) δ 168.05; 167.55; 161.46; 159.48; 158.84; 140.24; 132.54;130.17; 130.05; 129.23; 128.64; 128.42; 118.58; 114.73; 114.28; 69.50;55.57; 32.19; 27.03; 22.03; 13.63. HRMS (EI) m/z calculated: C₂₈H₂₉N₃O₂439.2260; found: 439.2266.

Example 9 4-(4-((4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine(1i)

Compound 1i was prepared according to the procedure in Example 1 from4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.98 mmol, 1 equivalent) and4-((4-chlorobenzyl)oxy) phenylboronic acid (360 mg, 1.37 mmol, 1.4equivalent) as a white amorphous solid (yield 123 mg, 32%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.28-8.04 (m, 4H, ArH); 7.66 (s, 1H,HetArH); 7.58-7.37 (m, 7H, ArH); 7.15 (d, J=9.0 Hz, 2H, ArH); 6.67 (s,2H, NH₂); 5.21 (s, 2H, CH₂). ¹³C NMR (100 MHz, DMSO-d₆) δ 165.02;164.78; 164.37; 160.58; 137.93; 136.38; 130.78; 130.06; 129.03; 128.93;127.39; 125.80; 124.63; 115.26; 101.56; 68.96. HRMS (EI) m/z calculated:C₂₃H₁₉ON₃Cl 388.112112; found: 388.12121.

Example 105-butyl-4-(4-((4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine (1j)

Compound 1j was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.76 mmol, 1equivalent) and 4-((4-chlorobenzyl)oxy) phenylboronic acid (278 mg, 1.06mmol, 1.4 equivalent) as a white amorphous solid (yield 241 mg, 71%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.41 (m, 11H, ArH); 7.12-7.07 (m, 2H,ArH); 6.47 (s, 2H, NH₂); 5.18 (s, 2H, O—CH₂—Ar); 1.01-0.91 (m, 2H,CH₂—CH₂—CH₂); 0.89-0.78 (m, 2H, CH₂—CH₂—CH₃); 0.46 (t, J=7.3 Hz, 3H,CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.06; 167.51; 161.47; 158.55;140.22; 136.47; 132.89; 132.80; 130.21; 130.03; 128.90; 128.64; 128.43;118.59; 114.77; 68.85; 32.18; 27.01; 22.03; 13.1. HRMS (EI) m/zcalculated: C₂₇H₂₆N₃OCl 443.1764; found: 443.1768.

Example 114-(4-(benzyloxy)-2-methylphenyl)-5-butyl-6-phenylpyrimidin-2-amine (1k)

Compound 1k was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (100 mg, 0.38 mmol, 1equivalent) and 4-(4-(benzyloxy)-2-methylphenylboronic acid (129 mg,0.53 mmol, 1.4 equivalent) as a white amorphous solid (yield 137 mg,85%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.50-7.31 (m, 10H, ArH); 7.13 (d, J=8.4 Hz,1H, ArH); 6.97 (d, J=2.5 Hz, 1H, ArH); 6.90 (dd, J=8.4, 2.6 Hz, 1H,ArH); 6.47 (s, 2H, NH₂); 5.14 (s, 2H, O—CH₂—Ar); 2.13 (s, 3H, CH₃—Ar);1.00-0.89 (m, 2H, CH₂—CH₂—CH₂); 0.86-0.76 (m, 2H, CH₂—CH₂—CH₃); 0.44 (t,J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.51; 167.68;161.58; 158.25; 140.08; 137.55; 136.68; 132.29; 129.70; 128.87; 128.70;128.62; 128.45; 128.25; 128.13; 119.42; 116.57; 112.06; 69.57; 32.04;27.01; 22.02; 19.96; 13.59. HRMS (EI) m/z calculated: C₂₈H₂₉N₃O423.2311; found: 423.2314.

Example 124-(4-(benzyloxy)-2,3-difluorophenyl)-6-phenylpyrimidin-2-amine (1l)

Compound 1l was prepared according to the procedure in Example 1 from4-chloro-6-phenylpyrimidin-2-amine (21 mg, 0.1 mmol, 1 equivalent) and4-(benzyloxy)-2,3-difluorophenylboronic acid (36 mg, 0.14 mmol, 1.4equivalent) as a white amorphous solid (yield 38 mg, 97%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.13-8.08 (m, 2H, ArH); 7.79 (td, J=8.7, 2.3Hz, 1H, ArH); 7.56-7.49 (m, 5H, ArH); 7.47-7.35 (m, 4H, ArH+HetArH);7.34-7.27 (m, 1H, ArH); 6.84 (s, 2H, NH₂); 5.32 (s, 2H, O—CH₂—Ar). ¹³CNMR (100 MHz, DMSO-d₆) δ 165.26; 164.36; 161.10; 137.55; 136.38; 131.05;129.21; 129.05; 128.78; 128.48; 127.31; 124.82; 110.91; 105.53; 105.45;71.29. HRMS (EI) m/z calculated: C₂₃H₁₇N₃OF₂ 389.1340; found: 389.1345.

Example 134-(4-(benzyloxy)-2,3-difluorophenyl)-5-butyl-6-phenylpyrimidin-2-amine(1m)

Compound 1m was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (100 mg, 0.38 mmol, 1equivalent) and 4-(benzyloxy)-2,3-difluorophenylboronic acid (140 mg,0.53 mmol, 1.4 equivalent) as a white amorphous solid (yield 42 mg,25%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.34 (m, 10H, ArH); 7.24-7.20 (m, 2H,ArH); 6.64 (s, 2H, NH₂); 5.30 (s, 2H, O—CH₂—Ar); 1.01-0.91 (m, 2H,CH₂—CH₂—CH₂); 0.90-0.79 (m, 2H, CH₂—CH₂—CH₃); 0.45 (t, J=7.2 Hz, 3H,CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.10; 162.16; 162.13; 161.69;139.68; 136.48; 129.01; 128.90; 128.70; 128.57; 128.53; 128.41; 124.97;124.92; 121.59; 121.45; 119.90; 111.12; 71.27; 32.12; 27.00; 21.92;13.54. HRMS (EI) m/z calculated: C₂₇H₂₅N₃OF₂ 445.1966; found: 445.1964.

Example 145-butyl-4-(4-((2-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine(1n)

Compound 1n was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.76 mmol, 1equivalent) and 4-((2-chlorobenzyl)oxy)-3,5-dimethylphenylboronic acid(308 mg, 1.06 mmol, 1.4 equivalent) as a white amorphous solid (yield349 mg, 97%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.69-7.65 (m, 1H, ArH); 7.56-7.51 (m, 1H,ArH); 7.50-7.41(m, 7H, ArH); 7.19 (s, 2H, ArH); 6.48 (s, 2H, NH₂); 4.96(s, 2H, O—CH₂—Ar); 2.27 (s, 6H, Ar—CH₃); 1.05-0.94 (m, 2H, CH₂—CH₂—CH₂);0.94-0.81 (m, 2H, CH₂—CH₂—CH₃), 0.50 (t, J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR(100 MHz, DMSO-d₆) δ 168.04; 167.66; 161.44; 155.50; 140.21; 135.85;135.28; 133.12; 131.06; 130.69; 130.45; 129.80; 129.27; 128.66; 128.62;128.44; 127.88; 118.57; 71.16; 32.23; 26.96; 22.02; 16.57; 13.56. HRMS(ESI) [M+H]⁺ m/z calculated: C₂₉H₃₁N₃OCl 472.2150; found: 472.2150.

Example 155-butyl-4-(4-((3-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine(1o)

Compound 1o was prepared according to the procedure in Example 1 from5-butyl-4-chloro-6-phenylpyrimidin-2-amine (200 mg, 0.76 mmol, 1equivalent) and 44(3-chlorobenzyl)oxy)-3,5-dimethylphenylboronic acid(308 mg, 1.06 mmol, 1.4 equivalent) as a white amorphous solid (yield336 mg, 94%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.41 (m, 9H, ArH); 7.20 (s, 2H, ArH);6.48 (s, 2H, NH₂); 4.89 (s, 2H, O—CH₂—Ar); 2.28 (s, 6H, Ar—CH₃);1.06-0.95 (m, 2H, CH₂—CH₂—CH₂); 0.94-0.82 (m, 2H, CH₂—CH₂—CH₃); 0.50 (t,J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 168.05; 167.65;161.44; 155.50; 140.48; 140.21; 135.82; 133.48; 130.81; 130.63; 129.29;128.67; 128.61; 128.44; 128.30; 128.02; 126.93; 118.56; 72.88; 32.22;26.96, 22.01; 16.63; 13.57. HRMS (ESI) [H+H]⁺ m/z calculated:C₂₉H₃₁N₃OCl 472.2150; found: 472.2150.

Example 164-(4-(benzyloxy)phenyl)-5-butyl-6-(3-methoxyphenyl)pyrimidin-2-amine(2a)

Compound 2a was prepared according to the procedure in Example 1 from4-(4-(benzyloxy)phenyl)-5-butyl-6-chloropyrimidin-2-amine (200 mg, 0.54mmol, 1 equivalent) a 3-methoxyphenylboronic acid (148 mg, 0.97 mmol,1.8 equivalent) as a white amorphous solid (yield 132 mg, 56%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.53-7.30 (m, 8H, ArH); 7.14-7.07 (m, 2H,ArH); 7.06-6.96 (m, 3H, ArH); 6.47 (s, 2H, NH₂); 5.17 (s, 2H, CH₂); 3.79(s, 3H, CH₃); 1.07-0.93 (m, 2H, CH₂—CH₂—CH₂); 0.92-0.79 (m, 2H,CH₂—CH₂—CH₃); 0.49 (t, J=7.3 Hz, 3H, CH₂—CH₃). ¹³C NMR (100 MHz,DMSO-d₆) δ 167.84; 167.55; 161.44; 159.30; 158.77; 141.59; 137.40;132.67; 130.19; 129.59; 128.90; 128.32; 128.21; 120.93; 118.58; 114.71;69.71; 55.65; 32.24; 27.08; 22.07; 13.66. HRMS (EI) m/z calculated:C₂₈H₃₀O₂N₃ 440.23325; found: 440.23321.

Example 174-(4-(benzyloxy)phenyl)-5-butyl-6-(4-methoxyphenyl)pyrimidin-2-amin (2b)

Compound 2b was prepared according to the procedure in Example 1 from4-(4-(benzyloxy)phenyl)-5-butyl-6-chloropyrimidin-2-amine (200 mg, 0.54mmol, 1 equivalent) a 4-methoxyphenylboronic acid (148 mg, 0.97 mmol,1.8 equivalent) as a white amorphous solid (yield 161 mg, 68%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.30 (m, 9H, ArH) 7.14-7.07 (m, 2H,ArH); 7.06-6.97 (m, 2H, ArH); 6.41 (s, 2H, NH₂); 5.17 (s, 2H, CH₂); 3.81(s, 3H, CH₃); 2.60-2.53 (m, 2H, HetAr—CH₂—CH₂); 1.02-0.92 (m, 2H,CH₂—CH₂—CH₂); 0.91-0.80 (m, 2H, CH₂—CH₂—CH₃); 0.49 (t, J=7.3 Hz, 3H,CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.56; 161.47; 159.66; 158.73;137.41; 132.83; 130.22; 128.89; 128.32; 128.21; 118.57; 114.69; 113.77;69.70; 55.61; 32.13; 27.13; 22.02; 13.70. HRMS (EI) m/z calculated:C₂₈H₃₀O₂N₃ 440.23325; found: 440.23322.

Example 184-(4-(benzyloxy)phenyl)-5-butyl-6-(3-chlorophenyl)pyrimidin-2-amine (2c)

Compound 2c was prepared according to the procedure in Example 1 from4-(4-(benzyloxy)phenyl)-5-butyl-6-chloropyrimidin-2-amine (200 mg, 0.54mmol, 1 equivalent) a 3-chlorophenylboronic acid (152 mg, 0.97 mmol, 1.8equivalent) as a white amorphous solid (yield 145 mg, 61%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.59-7.28 (m, 8H, ArH); 7.10 (d, J=8.7 Hz,2H, ArH); 6.55 (s, 2H, NH₂); 5.17 (s, 2H, CH₂), 0.97 (d, J=7.9 Hz, 2H,CH₂—CH₂—CH₂); 0.87 (q, J=7.1 Hz, 2H, CH₂—CH₂—CH₃); 0.49 (t, J=7.2 Hz,3H, CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.85 166.36; 116.15;158.86; 142.23; 137.38; 133.21; 132.49; 130.45; 13022; 128.90; 128.65;128.58; 128.33; 128.22; 127.44; 118.56; 114.74; 69.72; 32.14; 26.96;21.99; 13.60.

HRMS (EI) m/z calculated: C₂₇H₂₇ON₃Cl 444.18372; found: 444.18375.

Example 194-(4-(benzyloxy)phenyl)-5-butyl-6-(4-chlorophenyl)pyrimidin-2-amine (2d)

Compound 2d was prepared according to the procedure in Example 1 from4-(4-(benzyloxy)phenyl)-5-butyl-6-chloropyrimidin-2-amine (200 mg, 0.54mmol, 1 equivalent) a 4-chlorophenylboronic acid (152 mg, 0.97 mmol, 1.8equivalent) as a white amorphous solid (yield 148 mg, 62%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.66-7.20 (m, 12H, ArH); 7.17-7.04 (m, 2H,ArH); 6.53 (s, 2H, NH₂); 5.17 (s, 2H, CH₂); 1.02-0.91 (m, 2H,CH₂—CH₂—CH₂); 0.91-0.79 (m, 2H, CH₂—CH₂—CH₃); 0.49 (t, J=7.2 Hz, 3H,CH₂—CH₃). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.78; 166.74; 161.50; 158.83;139.05; 137.39, 133.44; 132.54; 130.66; 130.21; 128.90; 128.54; 128.33;128.22; 118.57; 114.73; 69.72; 32.16; 26.99; 22.00; 13.64. HRMS (EI) m/zcalculated: C₂₇H₂₇ON₃Cl 444.18372; found: 444.18367.

Results of Biological Assays

Production of PGE₂ was assayed in vitro in cultures of mouse peritonealcells. The cells (2×10⁶/mL) were stimulated with bacteriallipopolysaccharide (LPS, 10 ng/ml). Tested pyrimidine derivatives wereapplied at the concentration of 50 μmol.l⁻¹, concomitantly with LPS.Amount of PGE₂ in cell supernatants was determined 5 hours afterstimulation using the commercially available kit (R&D Systems). Theeffects of pyrimidines on PGE₂ production were evaluated in percent ofcontrol values, i.e. those found after the action of LPS alone (100%).The data in Table 2 show the remaining activity; the low values thusindicate strong inhibition of PGE₂ formation.

The concentrations required to inhibit PGE₂ biosynthesis by 50%(so-called IC₅₀) were determined by the analysis of concentration-effectexperiments. For this purpose, the compounds were applied within therange of 0.0004 μmol.l⁻¹ až 25 μmol.l⁻¹.

Cell viability was determined using the lactate dehydrogenase assay (LDHkit, Sigma-Aldrich). The mouse peritoneal cells were cultured for 5hours in the presence of tested compounds applied at the concentrationof 50 μmol.l⁻¹. The effects of pyrimidines were compared with theviability of cells cultured in the absence of the compounds. The laterwas taken as a control 100% viability. As a rule, the compounds did notexhibit any significant cytotoxicity. The only exception was 16 (2a),which reduced the viability to 43.1% of controls.

TABLE 2 Effect of tested pyrimidine derivatives (50 μmol · 1⁻¹) on thebiosynthesis of PGE₂ and viability of cells PGE₂ remaining IC₅₀ activityin (μmol · l⁻¹), and Cell viability Ex- % of LPS 95% limits of in % ofuntreated am- Com- response confidence (in controls ple pound (mean ±SEM) parentheses) (LDH assay) 1 1a 26.3 ± 0.1 (n = 8) not determined104.6 ± 1.3 (n = 8) 2 1b 12.3 ± 0.5 (n = 8) not determined 71.2 ± 1.9 (n= 8) 3 1e 10.1 ± 2.6 (n = 8) not determined 102.6 ± 0.6 (n = 8) 4 1d 0.7± 0.8 (n = 2) not determined 101.2 ± 0.7 (n = 4) 5 1e 0.3 ± 0.1 (n = 8)0.094 (0.045-0.197) 105.4 ± 0.2 (n = 8) 6 1f 26.3 ± 5.3 (n = 4) notdetermined 104.8 ± 0.4 (n = 8) 7 1g 8.4 ± 3.0 (n = 2) not determined99.6 ± 3.0 (n = 4) 8 1h 2.0 ± 1.5 (n = 4) 5.40 (3.89-7.50) 104.2 ± 0.3(n = 8) 9 1i 15.4/1.1 (n = 2) not determined 102.2 ± 4.1 (n = 4) 10 1j0.7 ± 0.5 n = 4) 0.077 (0.039-0.152) 101.2 ± 0.8 (n = 8) 11 1k 51.1 ±0.8 (n = 4) not determined 103.2 ± 0.5 (n = 8) 12 1l 5.5 ± 0.3 (n = 2)not determined 102.6 ± 3.7 (n = 4) 13 1m 0.03 ± 0.2 (n = 4) 0.006(0.003-0.011) 103.7 ± 0.4 (n = 8) 14 1n 7.1 ± 1.9 (n = 4) not determined103.6 ± 0.3 (n = 8) 15 1o 6.5 ± 0.4 (n = 4) not deterimined 102.8 ± 0.4(n = 8) 16 2a 10.0 ± 2.0 (n = 2) not determined 43.1 ± 8.4 (n = 4) 17 2b10.5 ± 0.1 (n = 2) not determined 100.3 ± 1.2 (n = 4) 18 2c 12.6 ± 1.7(n = 2) not determined 101.3 ± 2.0 (n = 4) 19 2d 4.1 ± 0.7 (n = 2) notdetermined 96.7 ± 2.2 (n = 4)

Similar to the PGE₂ assay, the production of nitric oxide (NO) wasfollowed under conditions in vitro using murine peritoneal cells (FIG.1). The cells (2×10⁶/ml) were cultured in presence of lipopolysaccharide(LPS, 0.1 ng/ml) and recombinant mouse interferon-γ (IFN-γ, 5 ng/ml).Effects of tested pyrimidine derivatives were screened at theconcentration of 50 μmol.l⁻¹. The compounds were added concomitantlywith LPS/IFN-γ. The concentration of nitrites in cell supernatants (ameasure of NO production) was evaluated spectrophotometrically, 24 hafter the priming stimuli. Griess reagent was used for this purpose. Theeffects of pyrimidines on NO production were evaluated in percent ofcontrol values, i.e those found after the action of LPS/IFN-γ alone(100%).

The tested pyrimidine derivatives exhibit a markedly enhanced inhibitoryselectivity towards the biosynthesis of PGE₂ (see Table 1). Theireffects on production of NO, which were assayed at the sameconcentration (i.e. 50 μmol.l⁻¹) were rather marginal (FIG. 1). This canbe exemplified by compound 1m (13). While it completely inhibits PGE₂production, the production of NO is lowered to 84% of controls only.

INDUSTRIAL APPLICABILITY

Due to the fact, that the pyrimidines derivatives shown here arenon-toxic inhibitors of PGE₂ production, they can be considered ascompounds suitable for the development of new medicament for thetreatment of inflammatory and tumor-related diseases.

1. Polysubstituted pyrimidines of the general formula

where X₁ to X₄ are the same or different substituents selected from thegroup comprising —H, —F, —Cl, alkyl Y₁ and Y₂ are the same or differentsubstituents selected from the group comprising —H, —F, —Cl, —OR,wherein R is alkyl; R₁ is, aryl as defined herein; R₂ is alkyl asdefined herein; or a pharmaceutically acceptable salt thereof, whereinalkyl in these cases is defined as a linear or branched C₁-C₁₀ carbonchain; aryl in the above cases is defined as a hydrocarbon groupcontaining 6 to 14 carbon atoms containing at least one aromatic ring,wherein the aryl may be unsubstituted or substituted with 1 to 5substituents selected from the group of —F, —Cl, —OR, wherein R is alkylas defined herein.
 2. The polysubstituted pyrimidines of the formula Iaccording to claim 1, selected from the group comprising:4-(4-(benzyloxy)phenyl)-6-phenylpyrimidin-2-amine4-(4-(benzyloxyphenyl)-5-butyl-6-phenylpyrimidin-2-amine5-butyl-4-(4-(naphthalen-1-ylmethoxy)phenyl)-6-phenylpyrimidin-2-amine4-(4-((4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine5-butyl-4-(4-((4-methoxybenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine4-(4-((4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine5-butyl-4-(4-((4-chlorobenzyl)oxy)phenyl)-6-phenylpyrimidin-2-amine4-(4-(benzyloxy)-2-methylphenyl)-5-butyl-6-phenylpyrimidin-2-amine4-(4-(benzyloxy)-2,3-difluorophenyl)-6-phenylpyrimidin-2-amine4-(4-(benzyloxy)-2,3-difluorophenyl)-5-butyl-6-phenylpyrimidin-2-amine5-butyl-4-(4-((2-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine5-butyl-4-(4-((3-chlorobenzyl)oxy)-3,5-dimethylphenyl)-6-phenylpyrimidin-2-amine4-(4-(benzyloxy)phenyl)-5-butyl-6-(3-methoxyphenyl)pyrimidin-2-amine4-(4-(benzyloxy)phenyl)-5-butyl-6-(4-methoxyphenyl)pyrimidin-2-amine4-(4-(benzyloxy)phenyl)-5-butyl-6-(3-chlorophenyl)pyrimidin-2-amine4-(4-(benzyloxy)phenyl)-5-butyl-6-(4-chlorophenyl)pyrimidin-2-amine andtheir pharmaceutically acceptable salts.
 3. A method of treatment,comprising the step of providing the polysubstituted pyrimidines of theformula I according to claim 1 as a medicament to a subject in needthereof.
 4. A method of inhibiting the overproduction of prostaglandinE₂ by providing the polysubstituted pyrimidines of the formula I asclaimed in claim 1 as a medicament to a subject in need thereof.
 5. Amethod of the treatment of diseases which are induced or their severityis increased by overproduction of prostaglandin E₂ by providing thepolysubstituted pyrimidines of the formula I according to claim 1 asmedicaments to subjects in need thereof, as anti-angiogenic,immunomodulatory, antiproliferative or anti-tumor drugs, for thetreatment of inflammatory and/or tumor diseases.
 6. A method oftreatment of diseases which are induced or their severity is increasedby the overproduction of prostaglandin E₂ by providing the substitutedpyrimidine of the formula I according to claim 1 as other activeingredients of a pharmaceutical composition, for the treatment ofinflammatory and/or tumor diseases.
 7. A pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof the formula I according to claim 1 and optionally at least onepharmaceutically acceptable carrier, filler and/or diluent and/oradjuvant.
 8. The pharmaceutical composition of claim 7 for use in thetreatment of diseases which are induced or their severity is increasedby overproduction of prostaglandin E₂, for the treatment of inflammatoryand/or tumor diseases.